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Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

A technology of dimethylcyclopropaneamide and heptenoic acid, which is applied in the field of key intermediates of cilastatin, and can solve the problem that the mixture is difficult to remove

Inactive Publication Date: 2008-06-18
WISCHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] However, the disadvantage of this method is that the hydrolysis not only produces unknown impurities after heating operation under acidic conditions, but also a considerable amount of the mixture is degraded into (S)-2,2-dimethyl ring which is difficult to remove in practice. Propanamide

Method used

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  • Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
  • Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid
  • Preparation method for (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid

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Effect test

Embodiment 1

[0030] Embodiment 1 (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ( 1 ) preparation

[0031] Get 200g (0.66mol) (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester ( 2 ), dissolved in 600ml of dichloromethane. 126 g of 4-toluenesulfonic acid was added to the mixture and stirred at 20°C. When analyzed according to gas chromatography, ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate ( 2 ) and (E)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester ( 3 ) at a (molar) ratio of about 200:1, the pH of the mixture was adjusted to 8-9 by adding 0.5N caustic soda solution and the organic phase was separated. The separated organic phase was concentrated under reduced pressure and added to 1,000 ml of acetonitrile. Next, add 1,420ml (0.925mol) of 0.65N caustic soda solution and stir at room temperature until (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2- Ethyl heptenoate ( 2 ) fully reacted...

Embodiment 2

[0034] Embodiment 2 (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ( 1 ) preparation

[0035] Get 100g (0.33mol) (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester ( 2 ), dissolved in 300ml toluene. 47 g of methanesulfonic acid was added to the mixture and stirred at 30°C. When analyzed according to gas chromatography, ethyl (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoate ( 2 ) and (E)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester ( 3 ) at a (molar) ratio of about 120:1, the reaction was terminated and the mixture was stirred. The pH of the mixture was adjusted to 8-9 by adding 0.5N caustic soda solution and the organic phase was separated. The separated organic phase was concentrated under reduced pressure and added to 300 ml of ethanol. Next, add 380ml (0.46mol) of 1.2N caustic soda solution and stir at room temperature until (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptyl...

Embodiment 3

[0038] The preparation of embodiment 3 cilastatin aqueous solution

[0039] Get (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid obtained in 34.4g embodiment 1 ( 1 ), be dissolved in the mixed aqueous solution of L-cysteine ​​hydrochloride (20g) and caustic soda solution (116ml), stir at room temperature. The reaction was continued until (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid ethyl ester according to high-speed liquid chromatography analysis ( 2 ) is completely consumed. As a result, a highly pure aqueous solution of cilastatin containing only a trace amount of the E isomer was obtained.

[0040] The method of removing isomeric impurities is very important in the preparation of key supplements of cilastatin-antibiotics such as imipenem. From this point of view, the process of the present invention is useful industrially, because the simple selective acid hydrolysis removes the A large amount of E isomer impurities in the preparat...

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Abstract

Provided is a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1), a key intermediate of cilastatin used as a supplement to imipenem. The novel preparation method of the invention produces a pure (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid, a key intermediate of cilastatin, by selective hydrolysis of E isomers.

Description

[0001] Cross References to Related Applications [0002] This application is based on and claims priority from Korean Patent Application No. 10-2006-125284 filed with the Korean Intellectual Property Office on December 11, 2006, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present invention relates to by following formula ( 1 ) represents a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid, which is used as an imipenem supplement The key intermediate of cilastatin. [0004] Background technique [0005] European Patent No. 48301, WO 2006 / 022511 and U.S. Patent Application No. 2005 / 0119346 described or referred to by the formula ( 1 ) represented by (Z)-7-chloro-((S)-2,2-dimethylcyclopropaneamido)-2-heptenoic acid or its inorganic salt of the conventional preparation process. [0006] According to the specification of WO 2006 / 022511, as shown in the following <rea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/63C07C231/18
CPCC07C2529/40C07C1/26C07C17/10C07C233/50C07C233/45
Inventor 赵阳来沈映址具彦澈郑善伊金炳焕
Owner WISCHEM
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